TY  - JOUR
AU  - Manojlović-Stojanoski, Milica
AU  - Lavrnja, Irena
AU  - Stevanović, Ivana
AU  - Trifunović, Svetlana
AU  - Ristić, Nataša
AU  - Nestorović, Nataša
AU  - Sévigny, Jean
AU  - Nedeljković, Nadežda
AU  - Laketa, Danijela
PY  - 2022
UR  - https://doi.org/10.1007/s10571-021-01081-8
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4187
AB  - Dexamethasone (DEX) is frequently used to treat women at risk of preterm delivery, but although indispensable for the completion of organ maturation in the fetus, antenatal DEX treatment may exert adverse sex-dimorphic neurodevelopmental effects. Literature findings implicated oxidative stress in adverse effects of DEX treatment. Purinergic signaling is involved in neurodevelopment and controlled by ectonucleotidases, among which in the brain the most abundant are ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) and ecto-5ʹ-nucleotidase (e5ʹNT/CD73), which jointly dephosphorylate ATP to adenosine. They are also involved in cell adhesion and migration, processes integral to brain development. Upregulation of CD39 and CD73 after DEX treatment was reported in adult rat hippocampus. We investigated the effects of maternal DEX treatment on CD39 and CD73 expression and enzymatic activity in the rat fetal brain of both sexes, in the context of oxidative status of the brain tissue. Fetuses were obtained at embryonic day (ED) 21, from Wistar rat dams treated with 0.5 mg DEX/kg/day, at ED 16, 17, and 18, and brains were processed and used for further analysis. Sex-specific increase in CD39 and CD73 expression and in the corresponding enzyme activities was induced in the brain of antenatally DEX-treated fetuses, more prominently in males. The oxidative stress induction after antenatal DEX treatment was confirmed in both sexes, although showing a slight bias in males. Due to the involvement of purinergic system in crucial neurodevelopmental processes, future investigations are needed to determine the role of these observed changes in the adverse effects of antenatal DEX treatment.
PB  - Springer
T2  - Cellular and Molecular Neurobiology
T1  - Antenatal Dexamethasone Treatment Induces Sex-dependent Upregulation of NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 in the Rat Fetal Brain
VL  - 42
DO  - 10.1007/s10571-021-01081-8
SP  - 1965
EP  - 1981
ER  - 

@article{
author = "Manojlović-Stojanoski, Milica and Lavrnja, Irena and Stevanović, Ivana and Trifunović, Svetlana and Ristić, Nataša and Nestorović, Nataša and Sévigny, Jean and Nedeljković, Nadežda and Laketa, Danijela",
year = "2022",
abstract = "Dexamethasone (DEX) is frequently used to treat women at risk of preterm delivery, but although indispensable for the completion of organ maturation in the fetus, antenatal DEX treatment may exert adverse sex-dimorphic neurodevelopmental effects. Literature findings implicated oxidative stress in adverse effects of DEX treatment. Purinergic signaling is involved in neurodevelopment and controlled by ectonucleotidases, among which in the brain the most abundant are ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) and ecto-5ʹ-nucleotidase (e5ʹNT/CD73), which jointly dephosphorylate ATP to adenosine. They are also involved in cell adhesion and migration, processes integral to brain development. Upregulation of CD39 and CD73 after DEX treatment was reported in adult rat hippocampus. We investigated the effects of maternal DEX treatment on CD39 and CD73 expression and enzymatic activity in the rat fetal brain of both sexes, in the context of oxidative status of the brain tissue. Fetuses were obtained at embryonic day (ED) 21, from Wistar rat dams treated with 0.5 mg DEX/kg/day, at ED 16, 17, and 18, and brains were processed and used for further analysis. Sex-specific increase in CD39 and CD73 expression and in the corresponding enzyme activities was induced in the brain of antenatally DEX-treated fetuses, more prominently in males. The oxidative stress induction after antenatal DEX treatment was confirmed in both sexes, although showing a slight bias in males. Due to the involvement of purinergic system in crucial neurodevelopmental processes, future investigations are needed to determine the role of these observed changes in the adverse effects of antenatal DEX treatment.",
publisher = "Springer",
journal = "Cellular and Molecular Neurobiology",
title = "Antenatal Dexamethasone Treatment Induces Sex-dependent Upregulation of NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 in the Rat Fetal Brain",
volume = "42",
doi = "10.1007/s10571-021-01081-8",
pages = "1965-1981"
}

Manojlović-Stojanoski, M., Lavrnja, I., Stevanović, I., Trifunović, S., Ristić, N., Nestorović, N., Sévigny, J., Nedeljković, N.,& Laketa, D.. (2022). Antenatal Dexamethasone Treatment Induces Sex-dependent Upregulation of NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 in the Rat Fetal Brain. in Cellular and Molecular Neurobiology
Springer., 42, 1965-1981.
https://doi.org/10.1007/s10571-021-01081-8

Manojlović-Stojanoski M, Lavrnja I, Stevanović I, Trifunović S, Ristić N, Nestorović N, Sévigny J, Nedeljković N, Laketa D. Antenatal Dexamethasone Treatment Induces Sex-dependent Upregulation of NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 in the Rat Fetal Brain. in Cellular and Molecular Neurobiology. 2022;42:1965-1981.
doi:10.1007/s10571-021-01081-8 .

Manojlović-Stojanoski, Milica, Lavrnja, Irena, Stevanović, Ivana, Trifunović, Svetlana, Ristić, Nataša, Nestorović, Nataša, Sévigny, Jean, Nedeljković, Nadežda, Laketa, Danijela, "Antenatal Dexamethasone Treatment Induces Sex-dependent Upregulation of NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 in the Rat Fetal Brain" in Cellular and Molecular Neurobiology, 42 (2022):1965-1981,
https://doi.org/10.1007/s10571-021-01081-8 . .

TY  - CONF
AU  - Laketa, Danijela
AU  - Manojlović-Stojanoski, Milica
AU  - Lavrnja, Irena
AU  - Stevanović, Ivana
AU  - Trifunović, Svetlana
AU  - Ristić, Nataša
AU  - Nestorović, Nataša
AU  - Sévigny, Jean
AU  - Nedeljković, Nadežda
PY  - 2021
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6209
AB  - To accelerate organ maturation and prevent complications due to preterm birth, antenatal treatment with
synthetic glucocorticoids (GCs – dexamethasone or betamethasone) is usually given between the 24th
and 34th week of pregnancy to women at risk of delivery within the next seven days [1]. Despite recommendations,
repeat courses of antenatal GCs are frequently given, although excessive GC stimulation may
exert adverse neurodevelopmental effects [1]. The purinergic system is essential for neurodevelopment
[2]. Extracellular purine levels are regulated by ectonucleotidases, with ectonucleoside triphosphate diphosphohydrolase
1 (NTPDase1/CD39) and ecto-5ʹ-nucleotidase (e5ʹNT/CD73), abundant in the CNS,
which jointly hydrolyze ATP to adenosine. Both ectonucleotidases are also involved in cell adhesion
and migration [3]. We aimed to explore the effects of antenatal dexamethasone (DEX) treatment on the
expression and enzymatic activity of NTPDase1/e5ʹNT tandem in the rat fetal brain. Wistar rat dams were
treated with 0.5 mg/kg DEX, at gestation day (GD) 16, 17, and 18. We found sex-specific male-biased
upregulation of CD39 and CD73 mRNA and protein abundances, and an increase in the corresponding enzymatic activities in the rat fetal brain at GD21, induced by antenatal DEX treatment. Observed changes
indicate a possible decrease in P2, and an increase in P1 purinergic receptors-mediated signaling, as
well as a potential decrease in migration of progenitor cells, particularly pronounced in the brain of male
fetuses. Together, sex-dependent induction of CD39 and CD73 might interfere with neurodevelopmental
processes, thus contributing to adverse effects of antenatal DEX treatment, especially in males.
PB  - Federation of European Neuroscience Societies
C3  - Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland
T1  - NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 are Upregulated in a Sex-specific fashion in the Rat Fetal Brain After Repeated Antenatal Dexamethasone Treatment
SP  - 192
EP  - 193
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6209
ER  - 

@conference{
author = "Laketa, Danijela and Manojlović-Stojanoski, Milica and Lavrnja, Irena and Stevanović, Ivana and Trifunović, Svetlana and Ristić, Nataša and Nestorović, Nataša and Sévigny, Jean and Nedeljković, Nadežda",
year = "2021",
abstract = "To accelerate organ maturation and prevent complications due to preterm birth, antenatal treatment with
synthetic glucocorticoids (GCs – dexamethasone or betamethasone) is usually given between the 24th
and 34th week of pregnancy to women at risk of delivery within the next seven days [1]. Despite recommendations,
repeat courses of antenatal GCs are frequently given, although excessive GC stimulation may
exert adverse neurodevelopmental effects [1]. The purinergic system is essential for neurodevelopment
[2]. Extracellular purine levels are regulated by ectonucleotidases, with ectonucleoside triphosphate diphosphohydrolase
1 (NTPDase1/CD39) and ecto-5ʹ-nucleotidase (e5ʹNT/CD73), abundant in the CNS,
which jointly hydrolyze ATP to adenosine. Both ectonucleotidases are also involved in cell adhesion
and migration [3]. We aimed to explore the effects of antenatal dexamethasone (DEX) treatment on the
expression and enzymatic activity of NTPDase1/e5ʹNT tandem in the rat fetal brain. Wistar rat dams were
treated with 0.5 mg/kg DEX, at gestation day (GD) 16, 17, and 18. We found sex-specific male-biased
upregulation of CD39 and CD73 mRNA and protein abundances, and an increase in the corresponding enzymatic activities in the rat fetal brain at GD21, induced by antenatal DEX treatment. Observed changes
indicate a possible decrease in P2, and an increase in P1 purinergic receptors-mediated signaling, as
well as a potential decrease in migration of progenitor cells, particularly pronounced in the brain of male
fetuses. Together, sex-dependent induction of CD39 and CD73 might interfere with neurodevelopmental
processes, thus contributing to adverse effects of antenatal DEX treatment, especially in males.",
publisher = "Federation of European Neuroscience Societies",
journal = "Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland",
title = "NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 are Upregulated in a Sex-specific fashion in the Rat Fetal Brain After Repeated Antenatal Dexamethasone Treatment",
pages = "192-193",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6209"
}

Laketa, D., Manojlović-Stojanoski, M., Lavrnja, I., Stevanović, I., Trifunović, S., Ristić, N., Nestorović, N., Sévigny, J.,& Nedeljković, N.. (2021). NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 are Upregulated in a Sex-specific fashion in the Rat Fetal Brain After Repeated Antenatal Dexamethasone Treatment. in Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland
Federation of European Neuroscience Societies., 192-193.
https://hdl.handle.net/21.15107/rcub_ibiss_6209

Laketa D, Manojlović-Stojanoski M, Lavrnja I, Stevanović I, Trifunović S, Ristić N, Nestorović N, Sévigny J, Nedeljković N. NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 are Upregulated in a Sex-specific fashion in the Rat Fetal Brain After Repeated Antenatal Dexamethasone Treatment. in Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland. 2021;:192-193.
https://hdl.handle.net/21.15107/rcub_ibiss_6209 .

Laketa, Danijela, Manojlović-Stojanoski, Milica, Lavrnja, Irena, Stevanović, Ivana, Trifunović, Svetlana, Ristić, Nataša, Nestorović, Nataša, Sévigny, Jean, Nedeljković, Nadežda, "NTPDase1/CD39 and Ecto-5ʹ-nucleotidase/CD73 are Upregulated in a Sex-specific fashion in the Rat Fetal Brain After Repeated Antenatal Dexamethasone Treatment" in Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland (2021):192-193,
https://hdl.handle.net/21.15107/rcub_ibiss_6209 .

TY  - JOUR
AU  - Božić, Iva
AU  - Savić, Danijela
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Laketa, Danijela
AU  - Milošević, Katarina
AU  - Bjelobaba, Ivana
AU  - Jakovljević, Marija
AU  - Nedeljković, Nadežda
AU  - Peković, Sanja
AU  - Lavrnja, Irena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5874
AB  - Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative disease with an autoimmune component. It was suggested that potassium channels, which are involved in crucial biological functions may have a role in different diseases, including MS and its animal model, experimental autoimmune encephalomyelitis (EAE). It was shown that voltage-gated potassium channels Kv1.5 are responsible for fine-tuning in the immune physiology and influence proliferation and differentiation in microglia and astrocytes. Here, we explored the cellular distribution of the Kv1.5 channel, together with its transcript and protein expression in the male rat spinal cord during different stages of EAE. Our results reveal a decrease of Kv1.5 transcript and protein level at the peak of disease, where massive infiltration of myeloid cells occurs, together with reactive astrogliosis and demyelination. Also, we revealed that the presence of this channel is not found in infiltrating macrophages/microglia during EAE. It is interesting to note that Kv1.5 channel is expressed only in resting microglia in the naïve animals. Predominant expression of Kv1.5 channel was found in the astrocytes in all experimental groups, while some vimentin+ cells, resembling macrophages, are devoid of Kv1.5 expression. Our results point to the possible link between Kv1.5 channel and the pathophysiological processes in EAE.
PB  - New York: Springer
T2  - Neurochemical Research
T1  - The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis
IS  - 12
VL  - 44
DO  - 10.1007/s11064-019-02892-4
SP  - 2733
EP  - 2745
ER  - 

@article{
author = "Božić, Iva and Savić, Danijela and Milošević, Ana and Janjić, Marija and Laketa, Danijela and Milošević, Katarina and Bjelobaba, Ivana and Jakovljević, Marija and Nedeljković, Nadežda and Peković, Sanja and Lavrnja, Irena",
year = "2019",
abstract = "Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative disease with an autoimmune component. It was suggested that potassium channels, which are involved in crucial biological functions may have a role in different diseases, including MS and its animal model, experimental autoimmune encephalomyelitis (EAE). It was shown that voltage-gated potassium channels Kv1.5 are responsible for fine-tuning in the immune physiology and influence proliferation and differentiation in microglia and astrocytes. Here, we explored the cellular distribution of the Kv1.5 channel, together with its transcript and protein expression in the male rat spinal cord during different stages of EAE. Our results reveal a decrease of Kv1.5 transcript and protein level at the peak of disease, where massive infiltration of myeloid cells occurs, together with reactive astrogliosis and demyelination. Also, we revealed that the presence of this channel is not found in infiltrating macrophages/microglia during EAE. It is interesting to note that Kv1.5 channel is expressed only in resting microglia in the naïve animals. Predominant expression of Kv1.5 channel was found in the astrocytes in all experimental groups, while some vimentin+ cells, resembling macrophages, are devoid of Kv1.5 expression. Our results point to the possible link between Kv1.5 channel and the pathophysiological processes in EAE.",
publisher = "New York: Springer",
journal = "Neurochemical Research",
title = "The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis",
number = "12",
volume = "44",
doi = "10.1007/s11064-019-02892-4",
pages = "2733-2745"
}

Božić, I., Savić, D., Milošević, A., Janjić, M., Laketa, D., Milošević, K., Bjelobaba, I., Jakovljević, M., Nedeljković, N., Peković, S.,& Lavrnja, I.. (2019). The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis. in Neurochemical Research
New York: Springer., 44(12), 2733-2745.
https://doi.org/10.1007/s11064-019-02892-4

Božić I, Savić D, Milošević A, Janjić M, Laketa D, Milošević K, Bjelobaba I, Jakovljević M, Nedeljković N, Peković S, Lavrnja I. The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis. in Neurochemical Research. 2019;44(12):2733-2745.
doi:10.1007/s11064-019-02892-4 .

Božić, Iva, Savić, Danijela, Milošević, Ana, Janjić, Marija, Laketa, Danijela, Milošević, Katarina, Bjelobaba, Ivana, Jakovljević, Marija, Nedeljković, Nadežda, Peković, Sanja, Lavrnja, Irena, "The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis" in Neurochemical Research, 44, no. 12 (2019):2733-2745,
https://doi.org/10.1007/s11064-019-02892-4 . .

TY  - CONF
AU  - Jakovljević, Marija
AU  - Lavrnja, Irena
AU  - Božić, Iva
AU  - Milošević, Ana
AU  - Bjelobaba, Ivana
AU  - Savić, Danijela
AU  - Peković, Sanja
AU  - Nedeljković, Nadežda
AU  - Laketa, Danijela
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5982
AB  - Considering neuroinflammatory paradigm, increased extracellular levels of ATP have adverse effects, while adenosine is predominantly anti-inflammatory. In the CNS, NTPDase1/CD39 is the main enzyme that initiates the degradation pathway of extracellular ATP to adenosine. The aim of the study was to explore the activation state of the cells that express NTPDase1/CD39 – microglia and macrophages, during experimental autoimmune encephalomyelitis (EAE). Acute monophasic EAE was induced in female Dark Agouti rats. Animals were sacrificed at the disease onset (Eo), peak (Ep) and end (Ee). The lumbosacral parts of spinal cords were isolated for gene (qRT-PCR and in situ hybridization) and protein expression analysis (Western Blot, immunofluorescence and flow cytometry). Activation state of microglia/macrophages was assessed by colocalization analysis of NTPDase1/Iba1 and NTPDase1/CD68 with iNOS or Arg1 as specific markers of pro- and antiinflammatory state, respectively. During EAE, NTPDase1/CD39 was significantly increased both at mRNA and protein level at Ep. Immunofluorescence combined with flow cytometry showed that reactive microglia and mononuclear infiltrates accounted for the most of the observed increase. Both Iba1 and CD68 microglia/macrophage markers showed higher co-occurrence with iNOS at Eo and Arg1 at Ep, suggesting prevalence of M1-like at Eo and M2-like at Ep. In addition, NTPDase1 showed about three-times higher colocalization with Arg1 compared to iNOS at Ep, suggesting its higher association with M2-like activation state of microglia/ macrophages. Together, our data suggest an association between NTPDase1 up-regulation by reactive microglia and infiltrated macrophages and their transition toward anti-inflammatory phenotype in EAE.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
T1  - NTPDase1/CD39 Expression Increased During EAE in Association with Number and Activation State of Microglia/Macrophages
SP  - 492
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5982
ER  - 

@conference{
author = "Jakovljević, Marija and Lavrnja, Irena and Božić, Iva and Milošević, Ana and Bjelobaba, Ivana and Savić, Danijela and Peković, Sanja and Nedeljković, Nadežda and Laketa, Danijela",
year = "2019",
abstract = "Considering neuroinflammatory paradigm, increased extracellular levels of ATP have adverse effects, while adenosine is predominantly anti-inflammatory. In the CNS, NTPDase1/CD39 is the main enzyme that initiates the degradation pathway of extracellular ATP to adenosine. The aim of the study was to explore the activation state of the cells that express NTPDase1/CD39 – microglia and macrophages, during experimental autoimmune encephalomyelitis (EAE). Acute monophasic EAE was induced in female Dark Agouti rats. Animals were sacrificed at the disease onset (Eo), peak (Ep) and end (Ee). The lumbosacral parts of spinal cords were isolated for gene (qRT-PCR and in situ hybridization) and protein expression analysis (Western Blot, immunofluorescence and flow cytometry). Activation state of microglia/macrophages was assessed by colocalization analysis of NTPDase1/Iba1 and NTPDase1/CD68 with iNOS or Arg1 as specific markers of pro- and antiinflammatory state, respectively. During EAE, NTPDase1/CD39 was significantly increased both at mRNA and protein level at Ep. Immunofluorescence combined with flow cytometry showed that reactive microglia and mononuclear infiltrates accounted for the most of the observed increase. Both Iba1 and CD68 microglia/macrophage markers showed higher co-occurrence with iNOS at Eo and Arg1 at Ep, suggesting prevalence of M1-like at Eo and M2-like at Ep. In addition, NTPDase1 showed about three-times higher colocalization with Arg1 compared to iNOS at Ep, suggesting its higher association with M2-like activation state of microglia/ macrophages. Together, our data suggest an association between NTPDase1 up-regulation by reactive microglia and infiltrated macrophages and their transition toward anti-inflammatory phenotype in EAE.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia",
title = "NTPDase1/CD39 Expression Increased During EAE in Association with Number and Activation State of Microglia/Macrophages",
pages = "492",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5982"
}

Jakovljević, M., Lavrnja, I., Božić, I., Milošević, A., Bjelobaba, I., Savić, D., Peković, S., Nedeljković, N.,& Laketa, D.. (2019). NTPDase1/CD39 Expression Increased During EAE in Association with Number and Activation State of Microglia/Macrophages. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 492.
https://hdl.handle.net/21.15107/rcub_ibiss_5982

Jakovljević M, Lavrnja I, Božić I, Milošević A, Bjelobaba I, Savić D, Peković S, Nedeljković N, Laketa D. NTPDase1/CD39 Expression Increased During EAE in Association with Number and Activation State of Microglia/Macrophages. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia. 2019;:492.
https://hdl.handle.net/21.15107/rcub_ibiss_5982 .

Jakovljević, Marija, Lavrnja, Irena, Božić, Iva, Milošević, Ana, Bjelobaba, Ivana, Savić, Danijela, Peković, Sanja, Nedeljković, Nadežda, Laketa, Danijela, "NTPDase1/CD39 Expression Increased During EAE in Association with Number and Activation State of Microglia/Macrophages" in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia (2019):492,
https://hdl.handle.net/21.15107/rcub_ibiss_5982 .

TY  - CONF
AU  - Laketa, Danijela
AU  - Jakovljević, Marija
AU  - Božić, Iva
AU  - Bjelobaba, Ivana
AU  - Savić, Danijela
AU  - Peković, Sanja
AU  - Nedeljković, Nadežda
AU  - Lavrnja, Irena
PY  - 2019
UR  - https://biore.bio.bg.ac.rs/handle/123456789/2265
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5893
AB  - Ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) is the main ATP- and ADPdegrading
enzyme in extracellular fluid of the central nervous system. In the hydrolysis cascade
NTPDase1 removes ATP and ADP and produces AMP, which is hydrolysed by ecto-5'-nucleotidase to
adenosine. During neuroinflammation, increased extracellular ATP levels exert proinflammatory effects
at microglia as resident immune cells, while adenosine effects are antiinflammatory. Literature data
indicate involvement of purinergic signaling in experimental autoimmune encephalomyelitis (EAE), while
decreased number of NTPDase1/CD39+ regulatory T-cells was evidenced in multiple sclerosis.
Downregulation of NTPDase1 expression was observed in proinflammatory activation phenotype of
macrophages. However, data on the role of NTPDase1 on glial cells in neuroinflammation are still
scarce. We have shown increase in ATP-, ADP- and AMP-hydrolysis, together with upregulated mRNA
and protein expression of NTPDase1 in lumbar spinal cord, correlated to the disease course during EAE.
In this study we aimed to explore contribution of particular cell subsets to the observed changes in
NTPDase1 expression.
Acute monophasic EAE was induced in female rats of Dark Agouti strain by active immunization with a
mixture of spinal cord homogenate in complete Freund’s adjuvant. Immunized animals were sacrificed at
the onset, peak and end of symptoms, while naïve animals were used as control. Significant increase of
NTPDase1 immunofluorescence in lumbar spinal cord cross-sections was related to prominent infiltrates
at the peak of EAE and increased expression of NTPDase1 among isolated mononuclear cells. Analysis
of triple-labeled Arginase1/NTPDase1/Iba1 and iNOS/NTPDase1/Iba1 immunofluorescent micrographs
showed prevalent contribution of Arginase1+ microglia in comparison to iNOS+ microglia in NTPDase1
immunofluorescence, at the peak of EAE. Further studies are needed to reveal possible association of
NTPDase1 with antiinflammatory phenotype in microglia.
PB  - German Neuroscience Society
C3  - Proceedings: 13th Göttingen Meeting of the German Neuroscience Society 2019 and 37th Göttingen Neurobiology Conference; 2019 Mar 20-23; Göttingen, Germany
T1  - Microglia-related increase in NTPDase1 expression during EAE
SP  - T12-5B
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5893
ER  - 

@conference{
author = "Laketa, Danijela and Jakovljević, Marija and Božić, Iva and Bjelobaba, Ivana and Savić, Danijela and Peković, Sanja and Nedeljković, Nadežda and Lavrnja, Irena",
year = "2019",
abstract = "Ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) is the main ATP- and ADPdegrading
enzyme in extracellular fluid of the central nervous system. In the hydrolysis cascade
NTPDase1 removes ATP and ADP and produces AMP, which is hydrolysed by ecto-5'-nucleotidase to
adenosine. During neuroinflammation, increased extracellular ATP levels exert proinflammatory effects
at microglia as resident immune cells, while adenosine effects are antiinflammatory. Literature data
indicate involvement of purinergic signaling in experimental autoimmune encephalomyelitis (EAE), while
decreased number of NTPDase1/CD39+ regulatory T-cells was evidenced in multiple sclerosis.
Downregulation of NTPDase1 expression was observed in proinflammatory activation phenotype of
macrophages. However, data on the role of NTPDase1 on glial cells in neuroinflammation are still
scarce. We have shown increase in ATP-, ADP- and AMP-hydrolysis, together with upregulated mRNA
and protein expression of NTPDase1 in lumbar spinal cord, correlated to the disease course during EAE.
In this study we aimed to explore contribution of particular cell subsets to the observed changes in
NTPDase1 expression.
Acute monophasic EAE was induced in female rats of Dark Agouti strain by active immunization with a
mixture of spinal cord homogenate in complete Freund’s adjuvant. Immunized animals were sacrificed at
the onset, peak and end of symptoms, while naïve animals were used as control. Significant increase of
NTPDase1 immunofluorescence in lumbar spinal cord cross-sections was related to prominent infiltrates
at the peak of EAE and increased expression of NTPDase1 among isolated mononuclear cells. Analysis
of triple-labeled Arginase1/NTPDase1/Iba1 and iNOS/NTPDase1/Iba1 immunofluorescent micrographs
showed prevalent contribution of Arginase1+ microglia in comparison to iNOS+ microglia in NTPDase1
immunofluorescence, at the peak of EAE. Further studies are needed to reveal possible association of
NTPDase1 with antiinflammatory phenotype in microglia.",
publisher = "German Neuroscience Society",
journal = "Proceedings: 13th Göttingen Meeting of the German Neuroscience Society 2019 and 37th Göttingen Neurobiology Conference; 2019 Mar 20-23; Göttingen, Germany",
title = "Microglia-related increase in NTPDase1 expression during EAE",
pages = "T12-5B",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5893"
}

Laketa, D., Jakovljević, M., Božić, I., Bjelobaba, I., Savić, D., Peković, S., Nedeljković, N.,& Lavrnja, I.. (2019). Microglia-related increase in NTPDase1 expression during EAE. in Proceedings: 13th Göttingen Meeting of the German Neuroscience Society 2019 and 37th Göttingen Neurobiology Conference; 2019 Mar 20-23; Göttingen, Germany
German Neuroscience Society., T12-5B.
https://hdl.handle.net/21.15107/rcub_ibiss_5893

Laketa D, Jakovljević M, Božić I, Bjelobaba I, Savić D, Peković S, Nedeljković N, Lavrnja I. Microglia-related increase in NTPDase1 expression during EAE. in Proceedings: 13th Göttingen Meeting of the German Neuroscience Society 2019 and 37th Göttingen Neurobiology Conference; 2019 Mar 20-23; Göttingen, Germany. 2019;:T12-5B.
https://hdl.handle.net/21.15107/rcub_ibiss_5893 .

Laketa, Danijela, Jakovljević, Marija, Božić, Iva, Bjelobaba, Ivana, Savić, Danijela, Peković, Sanja, Nedeljković, Nadežda, Lavrnja, Irena, "Microglia-related increase in NTPDase1 expression during EAE" in Proceedings: 13th Göttingen Meeting of the German Neuroscience Society 2019 and 37th Göttingen Neurobiology Conference; 2019 Mar 20-23; Göttingen, Germany (2019):T12-5B,
https://hdl.handle.net/21.15107/rcub_ibiss_5893 .

TY  - JOUR
AU  - Jakovljević, Marija
AU  - Lavrnja, Irena
AU  - Božić, Iva
AU  - Milošević, Ana
AU  - Bjelobaba, Ivana
AU  - Savić, Danijela
AU  - Sévigny, Jean
AU  - Peković, Sanja
AU  - Nedeljković, Nadežda
AU  - Laketa, Danijela
PY  - 2019
UR  - https://www.frontiersin.org/article/10.3389/fnins.2019.00410/full
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6498900
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3434
AB  - Purinergic signaling is critically involved in neuroinflammation associated with multiple sclerosis (MS) and its major inflammatory animal model, experimental autoimmune encephalomyelitis (EAE). Herein, we explored the expression of ectonucleoside triphosphate diphosphohydrolase1 (NTPDase1/CD39) in the spinal cord, at the onset (Eo), peak (Ep), and end (Ee) of EAE. Several-fold increase in mRNA and in NTPDase1 protein levels were observed at Eo and Ep. In situ hybridization combined with fluorescent immunohistochemistry showed that reactive microglia and infiltrated mononuclear cells mostly accounted for the observed increase. Colocalization analysis revealed that up to 80% of Iba1 immunoreactivity and ∼50% of CD68 immunoreactivity was colocalized with NTPDase1, while flow cytometric analysis revealed that ∼70% of mononuclear infiltrates were NTPDase1+ at Ep. Given the main role of NTPDase1 to degrade proinflammatory ATP, we hypothesized that the observed up-regulation of NTPDase1 may be associated with the transition between proinflammatory M1-like to neuroprotective M2-like phenotype of microglia/macrophages during EAE. Functional phenotype of reactive microglia/macrophages that overexpress NTPDase1 was assessed by multi-image colocalization analysis using iNOS and Arg1 as selective markers for M1 and M2 reactive states, respectively. At the peak of EAE NTPDase1 immunoreactivity showed much higher co-occurrence with Arg1 immunoreactivity in microglia and macrophages, compared to iNOS, implying its stronger association with M2-like reactive phenotype. Additionally, in ∼80% of CD68 positive cells NTPDase1 was coexpressed with Arg1 compared to negligible fraction coexpresing iNOS and ∼15% coexpresing both markers, additionally indicating prevalent association of NTPDase1 with M2-like microglial/macrophages phenotype at Ep. Together, our data suggest an association between NTPDase1 up-regulation by reactive microglia and infiltrated macrophages and their transition toward antiinflammatory phenotype in EAE.
T2  - Frontiers in Neuroscience
T1  - Induction of NTPDase1/CD39 by Reactive Microglia and Macrophages Is Associated With the Functional State During EAE.
VL  - 13
DO  - 10.3389/fnins.2019.00410
SP  - 410
ER  - 

@article{
author = "Jakovljević, Marija and Lavrnja, Irena and Božić, Iva and Milošević, Ana and Bjelobaba, Ivana and Savić, Danijela and Sévigny, Jean and Peković, Sanja and Nedeljković, Nadežda and Laketa, Danijela",
year = "2019",
abstract = "Purinergic signaling is critically involved in neuroinflammation associated with multiple sclerosis (MS) and its major inflammatory animal model, experimental autoimmune encephalomyelitis (EAE). Herein, we explored the expression of ectonucleoside triphosphate diphosphohydrolase1 (NTPDase1/CD39) in the spinal cord, at the onset (Eo), peak (Ep), and end (Ee) of EAE. Several-fold increase in mRNA and in NTPDase1 protein levels were observed at Eo and Ep. In situ hybridization combined with fluorescent immunohistochemistry showed that reactive microglia and infiltrated mononuclear cells mostly accounted for the observed increase. Colocalization analysis revealed that up to 80% of Iba1 immunoreactivity and ∼50% of CD68 immunoreactivity was colocalized with NTPDase1, while flow cytometric analysis revealed that ∼70% of mononuclear infiltrates were NTPDase1+ at Ep. Given the main role of NTPDase1 to degrade proinflammatory ATP, we hypothesized that the observed up-regulation of NTPDase1 may be associated with the transition between proinflammatory M1-like to neuroprotective M2-like phenotype of microglia/macrophages during EAE. Functional phenotype of reactive microglia/macrophages that overexpress NTPDase1 was assessed by multi-image colocalization analysis using iNOS and Arg1 as selective markers for M1 and M2 reactive states, respectively. At the peak of EAE NTPDase1 immunoreactivity showed much higher co-occurrence with Arg1 immunoreactivity in microglia and macrophages, compared to iNOS, implying its stronger association with M2-like reactive phenotype. Additionally, in ∼80% of CD68 positive cells NTPDase1 was coexpressed with Arg1 compared to negligible fraction coexpresing iNOS and ∼15% coexpresing both markers, additionally indicating prevalent association of NTPDase1 with M2-like microglial/macrophages phenotype at Ep. Together, our data suggest an association between NTPDase1 up-regulation by reactive microglia and infiltrated macrophages and their transition toward antiinflammatory phenotype in EAE.",
journal = "Frontiers in Neuroscience",
title = "Induction of NTPDase1/CD39 by Reactive Microglia and Macrophages Is Associated With the Functional State During EAE.",
volume = "13",
doi = "10.3389/fnins.2019.00410",
pages = "410"
}

Jakovljević, M., Lavrnja, I., Božić, I., Milošević, A., Bjelobaba, I., Savić, D., Sévigny, J., Peković, S., Nedeljković, N.,& Laketa, D.. (2019). Induction of NTPDase1/CD39 by Reactive Microglia and Macrophages Is Associated With the Functional State During EAE.. in Frontiers in Neuroscience, 13, 410.
https://doi.org/10.3389/fnins.2019.00410

Jakovljević M, Lavrnja I, Božić I, Milošević A, Bjelobaba I, Savić D, Sévigny J, Peković S, Nedeljković N, Laketa D. Induction of NTPDase1/CD39 by Reactive Microglia and Macrophages Is Associated With the Functional State During EAE.. in Frontiers in Neuroscience. 2019;13:410.
doi:10.3389/fnins.2019.00410 .

Jakovljević, Marija, Lavrnja, Irena, Božić, Iva, Milošević, Ana, Bjelobaba, Ivana, Savić, Danijela, Sévigny, Jean, Peković, Sanja, Nedeljković, Nadežda, Laketa, Danijela, "Induction of NTPDase1/CD39 by Reactive Microglia and Macrophages Is Associated With the Functional State During EAE." in Frontiers in Neuroscience, 13 (2019):410,
https://doi.org/10.3389/fnins.2019.00410 . .

TY  - JOUR
AU  - Božić, Iva
AU  - Milošević, Katarina
AU  - Laketa, Danijela
AU  - Adžić, Marija
AU  - Jakovljević, Marija
AU  - Bjelobaba, Ivana
AU  - Savić, Danijela
AU  - Nedeljković, Nadežda
AU  - Peković, Sanja
AU  - Lavrnja, Irena
PY  - 2018
UR  - http://link.springer.com/10.1007/s11064-018-2509-8
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3027
AB  - Kv1.3 is a voltage gated potassium channel that has been implicated in pathophysiology of multiple sclerosis (MS). In the present study we investigated temporal and cellular expression pattern of this channel in the lumbar part of spinal cords of animals with experimental autoimmune encephalomyelitis (EAE), animal model of MS. EAE was actively induced in female Dark Agouti rats. Expression of Kv1.3 was analyzed at different time points of disease progression, at the onset, peak and end of EAE. We here show that Kv1.3 increased by several folds at the peak of EAE at both gene and protein level. Double immunofluorescence analyses demonstrated localization of Kv1.3 on activated microglia, macrophages, and reactive astrocytes around inflammatory lesions. In vitro experiments showed that pharmacological block of Kv1.3 in activated astrocytes suppresses the expression of proinflammatory mediators, suggesting a role of this channel in inflammation. Our results support the hypothesis that Kv1.3 may be a therapeutic target of interest for MS and add astrocytes to the list of cells whose activation would be suppressed by inhibiting Kv1.3 in inflammatory conditions.
T2  - Neurochemical Research
T1  - Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis.
IS  - 5
VL  - 43
DO  - 10.1007/s11064-018-2509-8
SP  - 1020
EP  - 1034
ER  - 

@article{
author = "Božić, Iva and Milošević, Katarina and Laketa, Danijela and Adžić, Marija and Jakovljević, Marija and Bjelobaba, Ivana and Savić, Danijela and Nedeljković, Nadežda and Peković, Sanja and Lavrnja, Irena",
year = "2018",
abstract = "Kv1.3 is a voltage gated potassium channel that has been implicated in pathophysiology of multiple sclerosis (MS). In the present study we investigated temporal and cellular expression pattern of this channel in the lumbar part of spinal cords of animals with experimental autoimmune encephalomyelitis (EAE), animal model of MS. EAE was actively induced in female Dark Agouti rats. Expression of Kv1.3 was analyzed at different time points of disease progression, at the onset, peak and end of EAE. We here show that Kv1.3 increased by several folds at the peak of EAE at both gene and protein level. Double immunofluorescence analyses demonstrated localization of Kv1.3 on activated microglia, macrophages, and reactive astrocytes around inflammatory lesions. In vitro experiments showed that pharmacological block of Kv1.3 in activated astrocytes suppresses the expression of proinflammatory mediators, suggesting a role of this channel in inflammation. Our results support the hypothesis that Kv1.3 may be a therapeutic target of interest for MS and add astrocytes to the list of cells whose activation would be suppressed by inhibiting Kv1.3 in inflammatory conditions.",
journal = "Neurochemical Research",
title = "Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis.",
number = "5",
volume = "43",
doi = "10.1007/s11064-018-2509-8",
pages = "1020-1034"
}

Božić, I., Milošević, K., Laketa, D., Adžić, M., Jakovljević, M., Bjelobaba, I., Savić, D., Nedeljković, N., Peković, S.,& Lavrnja, I.. (2018). Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis.. in Neurochemical Research, 43(5), 1020-1034.
https://doi.org/10.1007/s11064-018-2509-8

Božić I, Milošević K, Laketa D, Adžić M, Jakovljević M, Bjelobaba I, Savić D, Nedeljković N, Peković S, Lavrnja I. Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis.. in Neurochemical Research. 2018;43(5):1020-1034.
doi:10.1007/s11064-018-2509-8 .

Božić, Iva, Milošević, Katarina, Laketa, Danijela, Adžić, Marija, Jakovljević, Marija, Bjelobaba, Ivana, Savić, Danijela, Nedeljković, Nadežda, Peković, Sanja, Lavrnja, Irena, "Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis." in Neurochemical Research, 43, no. 5 (2018):1020-1034,
https://doi.org/10.1007/s11064-018-2509-8 . .

TY  - CONF
AU  - Jakovljević, Marija
AU  - Lavrnja, Irena
AU  - Božić, Iva
AU  - Adžić, Marija
AU  - Bjelobaba, Ivana
AU  - Savić, Danijela
AU  - Peković, Sanja
AU  - Nedeljković, Nadežda
AU  - Laketa, Danijela
PY  - 2017
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5985
AB  - Introduction. Multiple sclerosis (MS) is a chronic disease of central nervous system (CNS), characterized by neuroinflammation, demyelination and neurodegeneration. Despite well-established role of purinergic signaling in MS pathology, the role of ADP as ectonucleotidase inter-product between proinflammatory ATP and anti-inflammatory adenosine is still obscure. Among ADP-sensitive receptors P2Y1, P2Y12 and P2Y13, there are few data indicating involvement of P2Y12 receptor in MS. The aim of this study was to elucidate a potential impact of ADP on CNS pathology in animal model of MS - experimental autoimmune encephalomyelitis (EAE). Material and Methods. EAE was induced in 8-week old female rats of Dark Agouti strain. The abundance and localization of ADP receptors – P2Y1, P2Y12 and P2Y13 was analyzed in lumbosacral spinal cord tissue by real-time PCR, Western Blot and immunohistochemistry at different disease stages – onset (Eo), peak (Ep) and recovery (Er). Results. Results of this study show that ADP-sensing purinergic receptors are differentially regulated during EAE. Namely, mRNA and protein expression of P2Y1 and P2Y12was decreased at Eo, while significantly increased for P2Y12and P2Y13 at Ep and/or Er. In addition, immunohistochemical labeling showed similar pattern of changes during EAE for investigated receptors, thus providing novel insight into their spinal cord tissue distribution. Conclusion. Our results strongly indicate involvement of ADP-sensitive purinergic receptors P2Y1, P2Y12 and P2Y13 in pathophysiology of EAE. Their differential regulation and tissue distribution implies diverse effects in the course of the disease during EAE. Further studies would be necessary to elucidate their mechanisms of action.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia
T1  - ADP receptors P2Y1, P2Y12 and P2Y13 are differentially regulated in a rat model of multiple sclerosis
SP  - 68
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5985
ER  - 

@conference{
author = "Jakovljević, Marija and Lavrnja, Irena and Božić, Iva and Adžić, Marija and Bjelobaba, Ivana and Savić, Danijela and Peković, Sanja and Nedeljković, Nadežda and Laketa, Danijela",
year = "2017",
abstract = "Introduction. Multiple sclerosis (MS) is a chronic disease of central nervous system (CNS), characterized by neuroinflammation, demyelination and neurodegeneration. Despite well-established role of purinergic signaling in MS pathology, the role of ADP as ectonucleotidase inter-product between proinflammatory ATP and anti-inflammatory adenosine is still obscure. Among ADP-sensitive receptors P2Y1, P2Y12 and P2Y13, there are few data indicating involvement of P2Y12 receptor in MS. The aim of this study was to elucidate a potential impact of ADP on CNS pathology in animal model of MS - experimental autoimmune encephalomyelitis (EAE). Material and Methods. EAE was induced in 8-week old female rats of Dark Agouti strain. The abundance and localization of ADP receptors – P2Y1, P2Y12 and P2Y13 was analyzed in lumbosacral spinal cord tissue by real-time PCR, Western Blot and immunohistochemistry at different disease stages – onset (Eo), peak (Ep) and recovery (Er). Results. Results of this study show that ADP-sensing purinergic receptors are differentially regulated during EAE. Namely, mRNA and protein expression of P2Y1 and P2Y12was decreased at Eo, while significantly increased for P2Y12and P2Y13 at Ep and/or Er. In addition, immunohistochemical labeling showed similar pattern of changes during EAE for investigated receptors, thus providing novel insight into their spinal cord tissue distribution. Conclusion. Our results strongly indicate involvement of ADP-sensitive purinergic receptors P2Y1, P2Y12 and P2Y13 in pathophysiology of EAE. Their differential regulation and tissue distribution implies diverse effects in the course of the disease during EAE. Further studies would be necessary to elucidate their mechanisms of action.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia",
title = "ADP receptors P2Y1, P2Y12 and P2Y13 are differentially regulated in a rat model of multiple sclerosis",
pages = "68",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5985"
}

Jakovljević, M., Lavrnja, I., Božić, I., Adžić, M., Bjelobaba, I., Savić, D., Peković, S., Nedeljković, N.,& Laketa, D.. (2017). ADP receptors P2Y1, P2Y12 and P2Y13 are differentially regulated in a rat model of multiple sclerosis. in Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 68.
https://hdl.handle.net/21.15107/rcub_ibiss_5985

Jakovljević M, Lavrnja I, Božić I, Adžić M, Bjelobaba I, Savić D, Peković S, Nedeljković N, Laketa D. ADP receptors P2Y1, P2Y12 and P2Y13 are differentially regulated in a rat model of multiple sclerosis. in Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia. 2017;:68.
https://hdl.handle.net/21.15107/rcub_ibiss_5985 .

Jakovljević, Marija, Lavrnja, Irena, Božić, Iva, Adžić, Marija, Bjelobaba, Ivana, Savić, Danijela, Peković, Sanja, Nedeljković, Nadežda, Laketa, Danijela, "ADP receptors P2Y1, P2Y12 and P2Y13 are differentially regulated in a rat model of multiple sclerosis" in Book of Abstract: 7th Congress of Serbian Neuroscience Society with international participation; 2017 Oct 25-27; Belgrade, Serbia (2017):68,
https://hdl.handle.net/21.15107/rcub_ibiss_5985 .

TY  - JOUR
AU  - Jakovljević, Marija
AU  - Lavrnja, Irena
AU  - Božić, Iva
AU  - Savić, Danijela
AU  - Bjelobaba, Ivana
AU  - Peković, Sanja
AU  - Sévigny, Jean
AU  - Nedeljković, Nadežda
AU  - Laketa, Danijela
PY  - 2017
UR  - http://journal.frontiersin.org/article/10.3389/fncel.2017.00333/full
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC5670145
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3152
AB  - The present study explores tissue and cellular distribution of ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2) and the gene and protein expression in rat spinal cord during the course of experimental autoimmune encephalomyelitis (EAE). Given that NTPDase2 hydrolyzes ATP with a transient accumulation of ADP, the expression of ADP-sensitive P2 purinoceptors was analyzed as well. The autoimmune disease was actively induced in Dark Agouti female rats and the changes were analyzed 10, 15 and 29 days after the induction. These selected time points correspond to the onset ( Eo ), peak ( Ep ) and recovery ( Er ) from EAE. In control animals, NTPDase2 was confined in the white matter, in most of the glial fibrillary acidic protein (GFAP)-immunoreactive (ir) astrocytes and in a considerable number of nestin-ir cells, while the other cell types were immunonegative. Immunoreactivity corresponding to NTPDase2 decreased significantly at Eo and Ep and then returned to the baseline levels at Er . The preservation of the proportion of GFAP single-labeled and GFAP/NTPDase2 double-labeled elements along the course of EAE indicated that changes in NTPDase2-ir occurred at fibrous astrocytes that typically express NTPDase2 in normal conditions. Significant downregulation of P2Y1 and P2Y12 receptor proteins at Eo and several-fold induction of P2Y12 and P2Y13 receptor proteins at Ep and/or Er were observed implying that the pathophysiological process in EAE may be linked to ADP signaling. Cell-surface expression of NTPDase2, NTPDase1/CD39 and ecto-5'-nucleotidase (eN/CD73) was analyzed in CD4+ T cells of a draining lymph node by fluorescence-activated cell sorting. The induction of EAE was associated with a transient decrease in a number of CD4+ NTPDase2+ T cells in a draining lymph node, whereas the recovery was characterized by an increase in NTPDase2+ cells in both CD4+ and CD4- cell populations. The opposite was found for NTPDase1/CD39+ and eN/CD73+ cells, which slightly increased in number with progression of the disease, particularly in CD4- cells, and then decreased in the recovery. Finally, CD4+ NTPDase2+ cells were never observed in the spinal cord parenchyma. Taken together, our results suggest that the process of neuroinflammation in EAE may be associated with altered ADP signaling.
T2  - Frontiers in Cellular Neuroscience
T1  - Down-regulation of NTPDase2 and ADP-sensitive P2 Purinoceptors Correlate with Severity of Symptoms during Experimental Autoimmune Encephalomyelitis.
VL  - 11
DO  - 10.3389/fncel.2017.00333
SP  - 333
ER  - 

@article{
author = "Jakovljević, Marija and Lavrnja, Irena and Božić, Iva and Savić, Danijela and Bjelobaba, Ivana and Peković, Sanja and Sévigny, Jean and Nedeljković, Nadežda and Laketa, Danijela",
year = "2017",
abstract = "The present study explores tissue and cellular distribution of ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2) and the gene and protein expression in rat spinal cord during the course of experimental autoimmune encephalomyelitis (EAE). Given that NTPDase2 hydrolyzes ATP with a transient accumulation of ADP, the expression of ADP-sensitive P2 purinoceptors was analyzed as well. The autoimmune disease was actively induced in Dark Agouti female rats and the changes were analyzed 10, 15 and 29 days after the induction. These selected time points correspond to the onset ( Eo ), peak ( Ep ) and recovery ( Er ) from EAE. In control animals, NTPDase2 was confined in the white matter, in most of the glial fibrillary acidic protein (GFAP)-immunoreactive (ir) astrocytes and in a considerable number of nestin-ir cells, while the other cell types were immunonegative. Immunoreactivity corresponding to NTPDase2 decreased significantly at Eo and Ep and then returned to the baseline levels at Er . The preservation of the proportion of GFAP single-labeled and GFAP/NTPDase2 double-labeled elements along the course of EAE indicated that changes in NTPDase2-ir occurred at fibrous astrocytes that typically express NTPDase2 in normal conditions. Significant downregulation of P2Y1 and P2Y12 receptor proteins at Eo and several-fold induction of P2Y12 and P2Y13 receptor proteins at Ep and/or Er were observed implying that the pathophysiological process in EAE may be linked to ADP signaling. Cell-surface expression of NTPDase2, NTPDase1/CD39 and ecto-5'-nucleotidase (eN/CD73) was analyzed in CD4+ T cells of a draining lymph node by fluorescence-activated cell sorting. The induction of EAE was associated with a transient decrease in a number of CD4+ NTPDase2+ T cells in a draining lymph node, whereas the recovery was characterized by an increase in NTPDase2+ cells in both CD4+ and CD4- cell populations. The opposite was found for NTPDase1/CD39+ and eN/CD73+ cells, which slightly increased in number with progression of the disease, particularly in CD4- cells, and then decreased in the recovery. Finally, CD4+ NTPDase2+ cells were never observed in the spinal cord parenchyma. Taken together, our results suggest that the process of neuroinflammation in EAE may be associated with altered ADP signaling.",
journal = "Frontiers in Cellular Neuroscience",
title = "Down-regulation of NTPDase2 and ADP-sensitive P2 Purinoceptors Correlate with Severity of Symptoms during Experimental Autoimmune Encephalomyelitis.",
volume = "11",
doi = "10.3389/fncel.2017.00333",
pages = "333"
}

Jakovljević, M., Lavrnja, I., Božić, I., Savić, D., Bjelobaba, I., Peković, S., Sévigny, J., Nedeljković, N.,& Laketa, D.. (2017). Down-regulation of NTPDase2 and ADP-sensitive P2 Purinoceptors Correlate with Severity of Symptoms during Experimental Autoimmune Encephalomyelitis.. in Frontiers in Cellular Neuroscience, 11, 333.
https://doi.org/10.3389/fncel.2017.00333

Jakovljević M, Lavrnja I, Božić I, Savić D, Bjelobaba I, Peković S, Sévigny J, Nedeljković N, Laketa D. Down-regulation of NTPDase2 and ADP-sensitive P2 Purinoceptors Correlate with Severity of Symptoms during Experimental Autoimmune Encephalomyelitis.. in Frontiers in Cellular Neuroscience. 2017;11:333.
doi:10.3389/fncel.2017.00333 .

Jakovljević, Marija, Lavrnja, Irena, Božić, Iva, Savić, Danijela, Bjelobaba, Ivana, Peković, Sanja, Sévigny, Jean, Nedeljković, Nadežda, Laketa, Danijela, "Down-regulation of NTPDase2 and ADP-sensitive P2 Purinoceptors Correlate with Severity of Symptoms during Experimental Autoimmune Encephalomyelitis." in Frontiers in Cellular Neuroscience, 11 (2017):333,
https://doi.org/10.3389/fncel.2017.00333 . .

TY  - JOUR
AU  - Parabucki, Ana
AU  - Savić, Danijela
AU  - Laketa, Danijela
AU  - Peković, Sanja
AU  - Stojiljković, Mirjana
AU  - Nedeljković, Nadežda
AU  - Bjelobaba, Ivana
PY  - 2014
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5864
AB  - Ectonucleotidases are cell surface-located enzymes responsible for the extracellular degradation of nucleotides. They are comprised of several protein families: ectonucleoside triphosphate diphosphohydrolases (E-NTPDase), ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPases) and ecto-5'-nucleotidase. Previously we showed that cortical stab injury alters ectonucleotidase activities in the rat brain, but that the specific enzymes responsible for these changes were not identified. In this study we investigated the gene expression of the specific ectonucleotidase enzymes, NTP-Dase1-3, NPP1-3 and ecto-5'-nucleotidase, two and seven days after cortical stab injury in rats, using real-time PCR. Two days after the injury we observed only one significant change: the downregulation in NTPDase2 mRNA expression. Our results indicate that traumatic brain injury induces significant upregulation of NTPDasel, NTPDase2 and ecto-5'-nucleotidase transcripts, and the downregulation of NPP1, seven days after the injury. Thus, traumatic brain injury has diverse impacts on ectonucleotidases gene expression, which may be reflected in the enzyme activities and extracellular nucleotide concentrations in the perilesional tissue.
PB  - Belgrade: Serbian Biological Society
T2  - Archives of Biological Sciences
T1  - Expression of major ectonucleotidases after cortical stab brain injury in rats: A real-time PCR study
IS  - 1
VL  - 66
DO  - 10.2298/ABS1401148P
SP  - 149
EP  - 155
ER  - 

@article{
author = "Parabucki, Ana and Savić, Danijela and Laketa, Danijela and Peković, Sanja and Stojiljković, Mirjana and Nedeljković, Nadežda and Bjelobaba, Ivana",
year = "2014",
abstract = "Ectonucleotidases are cell surface-located enzymes responsible for the extracellular degradation of nucleotides. They are comprised of several protein families: ectonucleoside triphosphate diphosphohydrolases (E-NTPDase), ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPases) and ecto-5'-nucleotidase. Previously we showed that cortical stab injury alters ectonucleotidase activities in the rat brain, but that the specific enzymes responsible for these changes were not identified. In this study we investigated the gene expression of the specific ectonucleotidase enzymes, NTP-Dase1-3, NPP1-3 and ecto-5'-nucleotidase, two and seven days after cortical stab injury in rats, using real-time PCR. Two days after the injury we observed only one significant change: the downregulation in NTPDase2 mRNA expression. Our results indicate that traumatic brain injury induces significant upregulation of NTPDasel, NTPDase2 and ecto-5'-nucleotidase transcripts, and the downregulation of NPP1, seven days after the injury. Thus, traumatic brain injury has diverse impacts on ectonucleotidases gene expression, which may be reflected in the enzyme activities and extracellular nucleotide concentrations in the perilesional tissue.",
publisher = "Belgrade: Serbian Biological Society",
journal = "Archives of Biological Sciences",
title = "Expression of major ectonucleotidases after cortical stab brain injury in rats: A real-time PCR study",
number = "1",
volume = "66",
doi = "10.2298/ABS1401148P",
pages = "149-155"
}

Parabucki, A., Savić, D., Laketa, D., Peković, S., Stojiljković, M., Nedeljković, N.,& Bjelobaba, I.. (2014). Expression of major ectonucleotidases after cortical stab brain injury in rats: A real-time PCR study. in Archives of Biological Sciences
Belgrade: Serbian Biological Society., 66(1), 149-155.
https://doi.org/10.2298/ABS1401148P

Parabucki A, Savić D, Laketa D, Peković S, Stojiljković M, Nedeljković N, Bjelobaba I. Expression of major ectonucleotidases after cortical stab brain injury in rats: A real-time PCR study. in Archives of Biological Sciences. 2014;66(1):149-155.
doi:10.2298/ABS1401148P .

Parabucki, Ana, Savić, Danijela, Laketa, Danijela, Peković, Sanja, Stojiljković, Mirjana, Nedeljković, Nadežda, Bjelobaba, Ivana, "Expression of major ectonucleotidases after cortical stab brain injury in rats: A real-time PCR study" in Archives of Biological Sciences, 66, no. 1 (2014):149-155,
https://doi.org/10.2298/ABS1401148P . .

TY  - JOUR
AU  - Nedeljković, Nadežda
AU  - Bjelobaba, Ivana
AU  - Dacić, Sanja
AU  - Lavrnja, Irena
AU  - Peković, Sanja
AU  - Savić, Danijela
AU  - Vještica, Aleksandar
AU  - Rakić, Ljubisav
AU  - Stojiljković, Mirjana
PY  - 2006
UR  - https://onlinelibrary.wiley.com/doi/abs/10.1016/j.cellbi.2006.03.001
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3464
UR  - https://www.sciencedirect.com/science/article/abs/pii/S1065699506000643
AB  - The objective of this study was to examine the changes in the activity and expression of ectonucleotidase enzymes in the model of unilateral cortical stab injury (CSI) in rat. The activities of ecto-nucleoside triphosphate diphosphohydrolase 1 (NTPDase 1) and ecto 50-nucleotidase were assessed by measuring the levels of ATP, ADP and AMP hydrolysis in the crude membrane preparations obtained from injured left cortex, right cortex, left and right caudate nucleus, whole hippocampus and cerebellum. Significant increase in NTPDase and ecto 50-nucleotidase activities was observed in the injured cortex following CSI, whereas in other brain areas only an increase in ecto 50-nucleotidase activity was seen. Immunohistochemical analysis performed using antibodies specific to NTPDase 1 and ecto 50-nucleotidase demonstrated that CSI induced sig-nificant changes in enzyme expression around the injury site. Immunoreactivity patterns obtained for NTPDase 1 and ecto 50-nucleotidase were compared with those obtained for glial fibrillary acidic protein, as a marker of astrocytes and complement receptor type 3 (OX42), as a marker of microglia. Results suggest that up-regulation of ectonucleotidase after CSI is catalyzed by cells that activate in response to injury, i.e. cells immunopositive for NTPDase 1 were predominantly microglial cells, whereas cells immunopositive for ecto 50-nucleotidase were predominantly astrocytes.
PB  - Elsevier
T2  - Cell Biology International
T1  - Up-regulation of ectonucleotidase activity after cortical stab injury in rats
IS  - 6
VL  - 30
DO  - 10.1016/j.cellbi.2006.03.001
SP  - 541
EP  - 546
ER  - 

@article{
author = "Nedeljković, Nadežda and Bjelobaba, Ivana and Dacić, Sanja and Lavrnja, Irena and Peković, Sanja and Savić, Danijela and Vještica, Aleksandar and Rakić, Ljubisav and Stojiljković, Mirjana",
year = "2006",
abstract = "The objective of this study was to examine the changes in the activity and expression of ectonucleotidase enzymes in the model of unilateral cortical stab injury (CSI) in rat. The activities of ecto-nucleoside triphosphate diphosphohydrolase 1 (NTPDase 1) and ecto 50-nucleotidase were assessed by measuring the levels of ATP, ADP and AMP hydrolysis in the crude membrane preparations obtained from injured left cortex, right cortex, left and right caudate nucleus, whole hippocampus and cerebellum. Significant increase in NTPDase and ecto 50-nucleotidase activities was observed in the injured cortex following CSI, whereas in other brain areas only an increase in ecto 50-nucleotidase activity was seen. Immunohistochemical analysis performed using antibodies specific to NTPDase 1 and ecto 50-nucleotidase demonstrated that CSI induced sig-nificant changes in enzyme expression around the injury site. Immunoreactivity patterns obtained for NTPDase 1 and ecto 50-nucleotidase were compared with those obtained for glial fibrillary acidic protein, as a marker of astrocytes and complement receptor type 3 (OX42), as a marker of microglia. Results suggest that up-regulation of ectonucleotidase after CSI is catalyzed by cells that activate in response to injury, i.e. cells immunopositive for NTPDase 1 were predominantly microglial cells, whereas cells immunopositive for ecto 50-nucleotidase were predominantly astrocytes.",
publisher = "Elsevier",
journal = "Cell Biology International",
title = "Up-regulation of ectonucleotidase activity after cortical stab injury in rats",
number = "6",
volume = "30",
doi = "10.1016/j.cellbi.2006.03.001",
pages = "541-546"
}

Nedeljković, N., Bjelobaba, I., Dacić, S., Lavrnja, I., Peković, S., Savić, D., Vještica, A., Rakić, L.,& Stojiljković, M.. (2006). Up-regulation of ectonucleotidase activity after cortical stab injury in rats. in Cell Biology International
Elsevier., 30(6), 541-546.
https://doi.org/10.1016/j.cellbi.2006.03.001

Nedeljković N, Bjelobaba I, Dacić S, Lavrnja I, Peković S, Savić D, Vještica A, Rakić L, Stojiljković M. Up-regulation of ectonucleotidase activity after cortical stab injury in rats. in Cell Biology International. 2006;30(6):541-546.
doi:10.1016/j.cellbi.2006.03.001 .

Nedeljković, Nadežda, Bjelobaba, Ivana, Dacić, Sanja, Lavrnja, Irena, Peković, Sanja, Savić, Danijela, Vještica, Aleksandar, Rakić, Ljubisav, Stojiljković, Mirjana, "Up-regulation of ectonucleotidase activity after cortical stab injury in rats" in Cell Biology International, 30, no. 6 (2006):541-546,
https://doi.org/10.1016/j.cellbi.2006.03.001 . .

TY  - CHAP
AU  - Peković, Sanja
AU  - Dacić, Sanja
AU  - Nedeljković, Nadežda
AU  - Bjelobaba, Ivana
AU  - Filipović, Radmila
AU  - Milenković, Ivan
AU  - Lavrnja, Irena
AU  - Savić, Danijela
AU  - Jovanović, Saša
AU  - Rakić, Ljubisav
AU  - Stojiljković, Mirjana
PY  - 2006
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5871
AB  - Injury to the central nervous system (CNS) is one of the leading causes of death and invalidity among all people below the age of 45 for which there are no specific treatments. The insight into the molecular pathophysiology of brain dysfunctions after the injury will provide indications for new effective therapeutic approaches that will limit damage, slow cell death and promote repair. The aim of this review is to highlight molecular mechanisms underlining primary and secondary injury. The initial impact or primary injury induces elevation of extracellular concentration of neurotransmitters leading to changes in electrical properties of neuronal membrane, net influx of Ca2+ and activation of diverse cellular signaling pathways. To restore neuronal homeostasis, the activities and expression of a variety of enzymes involved in control of extracellular concentration of biogenic amines and purine nucleotides/nucleosides, as well as the membrane potential are altered. The CNS has a limited capacity of self-repair. However, there are indications that the neonatal brain has a greater capacity for recovery than adult brain. The well known pathological hallmark of CNS injury is formation of the glial scar, the major impediment to axonal regeneration. Recently, it was shown that treatment with the purine nucleoside analogues attenuates and delays the process of reactive gliosis, and thus may be a useful approach for improving neurological recovery from head injury.
PB  - Kerala, India: Research Signpost
T2  - Neurobiological studies – From genes to behavior 2006
T1  - Molecular basis of brain injury and repair
SP  - 143
EP  - 165
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5871
ER  - 

@inbook{
author = "Peković, Sanja and Dacić, Sanja and Nedeljković, Nadežda and Bjelobaba, Ivana and Filipović, Radmila and Milenković, Ivan and Lavrnja, Irena and Savić, Danijela and Jovanović, Saša and Rakić, Ljubisav and Stojiljković, Mirjana",
year = "2006",
abstract = "Injury to the central nervous system (CNS) is one of the leading causes of death and invalidity among all people below the age of 45 for which there are no specific treatments. The insight into the molecular pathophysiology of brain dysfunctions after the injury will provide indications for new effective therapeutic approaches that will limit damage, slow cell death and promote repair. The aim of this review is to highlight molecular mechanisms underlining primary and secondary injury. The initial impact or primary injury induces elevation of extracellular concentration of neurotransmitters leading to changes in electrical properties of neuronal membrane, net influx of Ca2+ and activation of diverse cellular signaling pathways. To restore neuronal homeostasis, the activities and expression of a variety of enzymes involved in control of extracellular concentration of biogenic amines and purine nucleotides/nucleosides, as well as the membrane potential are altered. The CNS has a limited capacity of self-repair. However, there are indications that the neonatal brain has a greater capacity for recovery than adult brain. The well known pathological hallmark of CNS injury is formation of the glial scar, the major impediment to axonal regeneration. Recently, it was shown that treatment with the purine nucleoside analogues attenuates and delays the process of reactive gliosis, and thus may be a useful approach for improving neurological recovery from head injury.",
publisher = "Kerala, India: Research Signpost",
journal = "Neurobiological studies – From genes to behavior 2006",
booktitle = "Molecular basis of brain injury and repair",
pages = "143-165",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5871"
}

Peković, S., Dacić, S., Nedeljković, N., Bjelobaba, I., Filipović, R., Milenković, I., Lavrnja, I., Savić, D., Jovanović, S., Rakić, L.,& Stojiljković, M.. (2006). Molecular basis of brain injury and repair. in Neurobiological studies – From genes to behavior 2006
Kerala, India: Research Signpost., 143-165.
https://hdl.handle.net/21.15107/rcub_ibiss_5871

Peković S, Dacić S, Nedeljković N, Bjelobaba I, Filipović R, Milenković I, Lavrnja I, Savić D, Jovanović S, Rakić L, Stojiljković M. Molecular basis of brain injury and repair. in Neurobiological studies – From genes to behavior 2006. 2006;:143-165.
https://hdl.handle.net/21.15107/rcub_ibiss_5871 .

Peković, Sanja, Dacić, Sanja, Nedeljković, Nadežda, Bjelobaba, Ivana, Filipović, Radmila, Milenković, Ivan, Lavrnja, Irena, Savić, Danijela, Jovanović, Saša, Rakić, Ljubisav, Stojiljković, Mirjana, "Molecular basis of brain injury and repair" in Neurobiological studies – From genes to behavior 2006 (2006):143-165,
https://hdl.handle.net/21.15107/rcub_ibiss_5871 .